Researchers discover path to brain cancer treatment

Duane Cross

Glioblastoma multiforme (GMB) — the most common malignant primary brain tumor — is known for its ability to relapse. Researchers at the University of Texas M. D. Anderson Cancer Center have identified a pathway by which cancer cells spread and grow in the brain, opening up new possibilities for treatment. [1]

Primary brain tumors arise from cells of the brain rather than metastasizing to the brain from other places in the body.

The M. D. Anderson researchers developed a glioblastoma model to locate glioma stem cells, which, like all stem cells, have the ability to become other cell types. The researchers discovered that the gene, WNT5A, when activated, allowed glioma stem cells to transition, leading to invasive tumor growth.

Inside Knowledge

Did You Know?

WNT5A Gene

The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene encodes a member of the WNT family that signals through both the canonical and non-canonical WNT pathways. This protein is a ligand for the seven transmembrane receptor frizzled-5 and the tyrosine kinase orphan receptor 2. This protein plays an essential role in regulating developmental pathways during embryogenesis. This protein may also play a role in oncogenesis.

Clinically, gliomas are divided into four grades:

Grade I — This is a separate group of tumors called juvenile pilocytic astrocytoma (JPA) and subependymoma. These are noninvasive and slow growing and can often be cured with surgery.

Grade II — These tumors do not have actively dividing cells or dead cells in the tumor, called necrosis, but show many abnormal cells. A Grade II tumor can be an astrocytoma, ependymoma, or oligodendroglioma.

Grade III — These tumors are given a grade based on the cell type. For example, anaplastic astrocytoma is a Grade III tumor that contains dividing cells but no dead cells. In contrast, anaplastic oligodendroglioma and anaplastic ependymoma are Grade III tumors that do have dead cells.

Grade IV — A Grade IV tumor is usually glioblastoma. Cells in the tumor are actively dividing. In addition, the tumor has blood vessel growth and areas of dead tissue. [2]

Because most patients with GBMs die of their disease in less than a year and essentially none has long-term survival, researchers have spent a lot of time on these tumors.

Furthermore, about 25 percent of patients with GBM have multiple or multicentric GBMs at autopsy. Although GBMs can be seen on MRI scans, the neoplastic cells extend far beyond the area of enhancement. Even with repeat surgeries for tumor recurrences, the patients die from tumor spread into vital regions of the brain. [3]

“The poor prognosis of glioblastoma relates to the near universal recurrence of tumors despite robust treatment including surgery, radiotherapy, and chemotherapy,” said Baoli Hu, Ph.D., a senior research scientist with M. D. Anderson. “Our study shows the potential for a new therapeutic strategy based on targeting the mechanisms allowing glioma to re-grow aggressively in the brain.”

Stuck in what amounts to cellular adolescence, these precursor cells accumulate, contributing to the variability among glioblastoma multiforme cells that make it so difficult to treat, said Jian Hu, Ph.D., instructor of Genomic Medicine at MD Anderson.

“This arrested development is driven by the GBM cells' plasticity — their stem-cell-like ability to produce many types of cells — and the breakdown of the cellular maturation process known as terminal differentiation,” said M. D. Anderson President Ronald DePinho, M.D.

By searching for genes missing from GBM cells, rather than mutated, the researchers discovered a key differentiation pathway whose absence fuels tumor growth.

“If glioblastoma cells were to undergo differentiation, the tumor would stop growing,” Hu said. “But we've shown that if the terminal differentiation circuitry is gone, they get stuck in the middle and produce many different cell types.”

Such cellular diversity, or heterogeneity, is a hallmark of cancer that helps it survive and progress. The “multiforme” in glioblastoma multiforme reflects the heterogeneity among and inside tumors. [4]

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